The drug compound having the adopted name Ivacaftor, has a chemical name N-(2,4-di-tert-butyl-5-hydroxyphenyl)-1,4-dihydro-4-oxoquinoline-3-carboxamide, and is represented by following Formula I:
Ivacaftor was approved by FDA and marketed by Vertex pharma for the treatment of cystic fibrosis under the brand name KALYDECO® in the form of 150 mg oral tablets and in combination with lumacaftor under the brand name ORKAMBI® in the form of 200 mg/125 mg tablets (Lumacaftor/Ivacaftor) for the treatment of cystic fibrosis.
U.S. Pat. No. 7,495,103 (“the '103 patent”) discloses modulators of ATP-binding cassette transporters such as ivacaftor. The '103 patent further discloses a process for the preparation of modulators of ATP-binding cassette transporters such as quinoline compounds; however, ivacaftor process was not specifically disclosed. The '103 patent process includes condensation of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid with aniline in presence of a coupling reagent such as 1-[bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU), N,N-diisopropylethylamine (DIEA) in dimethylformamide and then purifying the obtained compound by HPLC. The process disclosed in the '103 patent is schematically represented as follows:

U.S. Pat. No. 8,410,274 (“the '274 patent”) specifically discloses a process for preparation of ivacaftor, which involves condensation of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid with 5-amino-2,4-di-(tert-butyl)phenol in presence of a coupling reagent such as HBTU, triethylamine and dimethyl formamide to obtain ivacaftor. The process disclosed in the '274 patent is schematically represented as follows:

U.S. Pat. No. 8,476,442 (“the '442 patent”) discloses a process for preparation of ivacaftor, which involves the coupling of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid with hydroxyl protected amine intermediate in the presence of a coupling reagent such as propane phosphonic anhydride (T3P®) and pyridine followed by deprotection of hydroxyl protection group to obtain ivacaftor. The process disclosed in the '442 patent is schematically represented as follows:

China Patent publication No. 103044263 (“the '263 publication”) discloses a process for the preparation of ivacaftor, which involves the coupling of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid chloride with hydroxyl protected amine intermediate in the presence of triethylamine in methylene chloride followed by deprotection of the hydroxyl protection group to obtain ivacaftor. The process disclosed in the '263 publication is schematically represented as follows:

China Patent publication No. 103787968 (“the '968 publication”) discloses a process for the preparation of ivacaftor, which involves the coupling of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid ethyl ester with hydroxyl protected amine intermediate in the presence of ethanol followed by deprotection of hydroxyl protection group to obtain ivacaftor. The process disclosed in the '968 publication is schematically represented as follows:

PCT Publication No. WO2014/118805 (“the '805 publication”) discloses a process for the preparation of ivacaftor, which involves reaction of malonate intermediate with 5-amino-2,4-di-(tert-butyl)phenol to obtain ester intermediate and finally cyclized to obtain ivacaftor. The process disclosed in the '805 publication is schematically represented as follows:

PCT Publication No. WO2014/125506 (“the '506 publication”) discloses a process for the preparation of ivacaftor, which involves condensation of 1-benzyl-4-oxo-1,4-dihydroquinoline-3-carboxylic acid with 5-amino-2,4-di-(tert-butyl)phenol in the presence of an amide coupling reagent such as HATU in dimethylformamide and followed by deprotection to obtain ivacaftor. The process disclosed in the '506 publication is schematically represented as follows:

PCT Publication No. WO2014/135096 (“the '096 publication”) discloses a process for the preparation of ivacaftor by following methods:


PCT Publication No. WO2015/128882 (“the '882 publication”) discloses a process for the preparation of ivacaftor, which involves condensation of 4-oxo-1,4-dihydro-3-quinoline carboxylic acid with 5-amino-2,4-di-(tert-butyl)phenol in presence of a coupling reagent such as EDC HCl and HOBt, triethylamine and dimethyl formamide to obtain ivacaftor. The process disclosed in the '882 patent is schematically represented as follows:

CN Publication No. CN105130891A (“the '891 publication”) discloses a process for the preparation of ivacaftor. The process disclosed in the '891 publication is schematically represented as follows:

The reported literatures for the preparation of ivacaftor have certain drawbacks, which include use of coupling agents in the amide formation reaction. The use of coupling agents in such a reaction creates unwanted by-products as well as unreacted coupling agents as contaminants, thereby extensive purifications are required in order to eliminate such compounds from the pure product.
There is a need in the art to develop an improved process for the preparation of ivacaftor, which is readily amenable to large scale production. The present inventors focused improved processes for the preparation of ivacaftor with greater yield and higher purity, which process avoids the expensive coupling agents.